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Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women
D. Mehta, FC. Tropf, J. Gratten, A. Bakshi, Z. Zhu, SA. Bacanu, G. Hemani, PK. Magnusson, N. Barban, T. Esko, A. Metspalu, H. Snieder, BJ. Mowry, KS. Kendler, J. Yang, PM. Visscher, JJ. McGrath, MC. Mills, NR. Wray, SH. Lee, . , OA. Andreassen,...
Language English Country United States
Document type Journal Article
- MeSH
- Alleles MeSH
- Genome-Wide Association Study * MeSH
- Adult MeSH
- Phenotype MeSH
- Genetic Predisposition to Disease genetics MeSH
- Cohort Studies MeSH
- Humans MeSH
- Birth Order * MeSH
- Risk MeSH
- Schizophrenia genetics MeSH
- Pregnancy MeSH
- Maternal Age * MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Denmark MeSH
IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.
Center for Contextual Psychiatry Department of Neuroscience KU Leuven Leuven Belgium
Department of Genetics The Hebrew University of Jerusalem Jerusalem Israel
Department of Human Genetics David Geffen School of Medicine University of California Los Angeles
Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
Department of Medical Genetics Medical University Sofia Bulgaria
Department of Psychiatry Academic Medical Centre University of Amsterdam Amsterdam the Netherlands
Department of Psychiatry Hadassah Hebrew University Medical Center Jerusalem Israel
Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York
Department of Psychiatry Royal College of Surgeons in Ireland Dublin Ireland
Department of Psychiatry University College Cork Cork Ireland
Department of Psychiatry University of Colorado Denver Aurora
Department of Psychiatry University of Oxford Oxford England
Department of Psychiatry Washington University in St Louis St Louis Missouri
Department of Sociology Nuffield College University of Oxford Oxford England
Estonian Genome Center University of Tartu Tartu Estonia
Institute of Molecular Genetics Russian Academy of Sciences Moscow Russia
Molecular and Cellular Therapeutics Royal College of Surgeons in Ireland Dublin Ireland
Molecular Psychiatry Laboratory Division of Psychiatry University College London London England
Queensland Brain Institute The University of Queensland Brisbane Australia
Rheumatology Research Group Vall d'Hebron Research Institute Barcelona Spain
Sheba Medical Center Tel Hashomer Israel
References provided by Crossref.org
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